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Internal Medicine Journal 44 (2014)

Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014 L. Cooley,1 C. Dendle,2,3 J. Wolf,4,5 B. W. Teh,6 S. C. Chen,7,8,9 C. Boutlis10,11 and K. A. Thursky6,12 1 Department of Microbiology and Infectious Diseases, Royal Hobart Hospital, Hobart, Tasmania, 2Departments of Infectious Diseases and General Medicine, Monash Medical Centre, Monash Health, Clayton, Victoria, 3Southern Clinical School, Faculty of Medicine, Monash University, Melbourne, Victoria, 4Department of Infectious Diseases, St. Jude Children’s Research Center, Memphis, Tennessee, USA, 5University of Tennessee Health Sciences Center, Memphis, Tennessee, USA, 6Department of Infectious Diseases and Infection Control, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 7Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR – Pathology West, Westmead, New South Wales, 8 Department of Infectious Diseases, Westmead Hospital, Westmead, New South Wales, 9Sydney Medical School, The University of Sydney, Sydney, New South Wales, 10Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, 11Graduate School of Medicine, University of Wollongong, Wollongong, New South Wales, 12Victorian Infectious Diseases Service, The Doherty Institute for Infection and Immunity,

Parkville, Victoria

Key words Pneumocystis carinii, Pneumocystis jirovecii, haematological malignancy, solid-organ tumour, prophylaxis, treatment. Correspondence Karin Thursky, Department of Infectious Diseases, Peter MacCallum Cancer Centre, Locked Bag Number 1 A’Beckett Street, East Melbourne, Vic. 8006, Australia. Email: [email protected]

Abstract Pneumocystis jirovecii infection (PJP) is a common cause of pneumonia in patients with cancer-related immunosuppression. There are well-defined patients who are at risk of PJP due to the status of their underlying malignancy, treatment-related immunosuppression and/or concomitant use of corticosteroids. Prophylaxis is highly effective and should be given to all patients at moderate to high risk of PJP. Trimethoprimsulfamethoxazole is the drug of choice for prophylaxis and treatment, although several alternative agents are available.

doi:10.1111/imj.12599

Introduction Pneumocystis jirovecii infection causes pneumonia (PJP; also known as PCP) in patients with immunosuppression due to underlying malignancy, organ transplantation or other conditions. The infection is best studied in those with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome, as there are significant differences in the clinical features of PJP between HIVinfected and non-infected individuals.1–5 Infection in immunosuppressed HIV-negative individuals has a shorter duration of onset and fewer systemic symptoms than in HIV-infected individuals.1 Bronchoalveolar lavage fluid from immunosuppressed nonHIV-infected patients shows lower concentrations of organisms but higher inflammatory scores.6 Clinical

disease is generally more severe in these patients, with increased length of hospital stay and higher rates of intensive care unit (ICU) admission and mechanical ventilation, compared with HIV-infected patients.1–4 Significantly higher mortality rates are also observed in non-HIVinfected individuals (34–39%) compared to those with HIV (6–7%).1,5,7 With a focus on HIV-negative populations, this guideline outlines diagnostic approaches and provides recommendations for prophylaxis and treatment of PJP in adults and children undergoing chemotherapy for haematological and solid-organ tumours. It does not discuss P. jirovecii affecting extra-pulmonary sites or infection in the setting of organ transplantation.

Methodology Conflicts of interest: The following authors are consultants or advisory committee members or receive honoraria, fees for service, or travel assistance from, or have research or other associations with the organisations listed: Sharon Chen – Gilead, Merck Sharp & Dohme, Pfizer; Karin Thursky – Pfizer.

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Questions asked In preparing this update, we aimed to address the following questions: © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Guidelines for prevention and treatment of PJP

1 What are the current diagnostic strategies for PJP? 2 Which patients with haematological and solid malignancies are at risk for PJP? 3 What is the evidence for prophylaxis? Which agents are most effective? 4 What are the first- and second-line agents for treatment of PJP? 5 Is there any evidence to keep patients with confirmed PJP in clinical isolation?

Search strategy A literature review was performed using PubMed to identify papers published since 2007 that pertained to PJP in patients with haematological and solid tumours. Search terms included (in combination) ‘Pneumocystis carinii’, ‘Pneumocystis jirovecii’, ‘immunocompromised’, ‘non-HIV’, ‘treatment’, ‘prophylaxis’ and ‘diagnostics’.

Diagnosis of PJP Microbiological tests Due to difficulties with isolating and culturing this pathogen, microscopic examination of respiratory specimens using various staining methods is used to visualise and identify the morphological structures of P. jirovecii. Methenamine silver and toluidine blue preparations stain only the cyst wall and do not allow detection of trophozoites. However, Giemsa stains detect all life stages of P. jirovecii. Direct and indirect immunofluorescent assays (DFA, IFA) are specific for different life stages, depending on the antibody used. Comparative studies have shown DFA and IFA to be the most sensitive stains for P. jirovecii in sputum and bronchoalveolar lavage, with sensitivities of 97% and 90% respectively.8 These assays are also commercially available. Overall, the accuracy of staining methods is highly dependent on the quality of respiratory specimen, sample processing, reaction of the specimen to the stain chosen and experience of the laboratory observer. The lower burden of P. jirovecii in non-HIV-immunocompromised patients, and the likelihood that they may already be on anti-pneumocystis prophylaxis, remains a challenge for diagnosis.9 Staining methods have now largely been supplanted by highly sensitive molecular techniques, using semi- or fully quantitative polymerase chain reaction (PCR) targeting P. jirovecii-specific genes.10 A meta-analysis of PCR studies has shown a pooled sensitivity of 99% and specificity of 92% in the non-HIV patient population.11 A variety of gene targets can be used for PCR amplifi© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

cation, including: major surface glycoprotein (MSG) gene, mitochondrial large subunit (mtLSU) rRNA gene, dihydropteroate synthase (DHPS) gene, dihydrofolate reductase (DHFR) gene, heat shock protein (HSP) 70 gene and the beta-tubulin gene. Multicopy genes such as mtLSU and MSG offer the greatest sensitivity for P. jirovecii detection.10 However, they lack specificity and have a low positive predictive value due to the increased detection of P. jirovecii in patients who are colonised but otherwise well. With a high negative predictive value, PCR is best utilised for excluding the diagnosis of PJP.12 Quantitative PCR (qPCR), with defined upper- and lower-quantitation thresholds of P. jirovecii copy number, can be used to distinguish true infection from colonisation.13–18 However, there remains an indeterminate zone of unclear clinical significance.14–17 Further, these quantitation thresholds will vary between different patient populations; clinicians should be cautious of relying on them as a measure to guide diagnosis or therapy. To improve accuracy, combined diagnostic algorithms have been proposed. These use qPCR and β(1,3)-D-glucan on serum testing to classify patients into infection and colonisation categories,19 but validation is still required in patients with malignancy. Due to heterogeneity of methods and diversity of chosen qPCR targets in published literature, generalisability of reported cut-off values is limited. Each institution must establish and validate its own qPCR cut-off values appropriate to the preferred molecular method. While molecular tests may aid clinical diagnosis, there is a lack of correlation between qPCR and the clinical features or outcomes of PJP.20 Therefore, clinicians should take an individual’s clinical risk of PJP into consideration when interpreting the cycle thresholds. Studies on the use of molecular diagnosis have largely been based on bronchoalveolar lavage sampling.15,16 Although induced sputum samples have also been evaluated, they can be demanding to perform on wards and in children.17 Others have reported the use of oral washes and expectorated sputum, but the clinical validity of these approaches requires further evaluation.20,21 These approaches certainly produce a lower yield – that may be useful – but, overall, their value in this particular setting remains unclear.

Radiological findings Imaging studies are an essential companion to microbiological testing for diagnosing PJP. High-resolution computed tomography (CT) is the most commonly used and reliable radiological modality for detecting pneumonic 1351

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changes in immunocompromised patients.22 The most frequent CT findings are bilateral, ground-glass changes with apical predominance and peripheral sparing.22 In non-HIV-immunocompromised patients with PJP, signs of consolidation are detected more frequently on CT – and cystic changes less frequently – than in HIV-positive patients with PJP.23,24 The range of other radiological features seen in PJP include a combination of ground glass and consolidative opacities, cystic changes, linearreticular opacities, solitary or multiple nodules and parenchymal cavities.25 With treatment, the vast majority of these changes resolve.22 Nuclear imaging modalities such as 18Ffludeoxyglucose-positron emission tomography (FDGPET) have been used as an adjunct to plain X-ray or CT.26 The FDG-PET findings correlate well with conventional imaging, showing bilateral uptake of FDG in the upper zones of the lungs.27 Abnormalities on PET scans, leading to PJP diagnosis in the setting of normal chest radiographs, have been reported, which suggests a potential role for PET scans in facilitating early diagnosis. However, limited access to FDG-PET is currently a significant barrier to use.28

Determining patient risk and the need for PJP prophylaxis Antimicrobial prophylaxis is highly successful in preventing PJP in patients with immunosuppression from a diverse range of causes, including solid-organ transplantation and malignancy. Chemoprophylaxis was first demonstrated to be highly effective in preventing PJP in a randomised controlled study of paediatric oncology patients.29 Pooled data from 11 clinical trials showed a reduction in the relative risk (RR) of PJP (0.09, 95% confidence interval (CI) 0.02–0.32) in patients receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis compared with patients receiving no intervention, placebo or an antibiotic without PJP activity.30 TMPSMX prophylaxis has been shown to have a mortality benefit and its use is recommended in settings where the risk of PJP is estimated to exceed 3.5% (grade A recommendation).30 Prophylaxis is routinely used in children for a wider range of malignancies, including those with a lower risk of PJP, as TMP-SMX is very well tolerated. In patients with haematological malignancy, both host and disease factors, as well as chemotherapy regimens need to be considered when determining an individual’s risk of PJP (see Table 1). A patient’s risk of PJP is influenced by multiple factors at any given point in time and risk should be continually assessed throughout the treatment period. 1352

Table 1 Patients with malignancy at high risk for Pneumocystis jirovecii pneumonia • Heavily pre-treated patients (e.g. multiple lines of chemotherapy for Hodgkin and non-Hodgkin lymphoma, lymphoproliferative diseases or myeloma). • Relapsed disease. • High-dose corticosteroids (often in combination with chemotherapy). • Chemotherapy, monoclonal antibodies or diseases causing prolonged lymphopenia (e.g. ALL, alemtuzumab, R-CHOP14).

PJP risk in patients with haematological malignancy Specific patient groups with underlying haematological malignancy have been identified to be at high risk of PJP.31 These findings have been used to inform guidelines regarding institution of PJP prophylaxis. However, there have been important shifts in the treatment of haematological malignancies30,32 and diagnostic algorithms since the publication of earlier studies. Furthermore, early evaluation did not encompass emerging subgroups of patients with haematological malignancy. The estimated risk of PJP in these groups, such as acute myeloid leukaemia,3,33,34 myelodysplasia, myeloma3,35–37 and lymphoma,38–46 are based on case reports and are incompletely defined. The most easily quantifiable risk factors in patients with haematological malignancy are choice, dose and combination of chemotherapy agents. Other factors, such as age, comorbidities, type47 and stage of malignancy, surgery, radiation and immune parameters,45 also contribute to risk but are more difficult to quantify. Patients at highest risk of PJP are those undergoing treatment for acute lymphoblastic leukaemia (ALL) (up to 16%)48 and for allogeneic haemapoietic stem cell transplant (HSCT) (from 0.3% to 15%).3,49,50 In these populations, the number needed to treat has been estimated to be 11.30 Patients receiving prolonged, high-dose corticosteroid treatment (16–25 mg of prednisolone per day or ≥4 mg dexamethasone daily for ≥4 weeks) are also at high risk of PJP, regardless of underlying type or stage of malignancy, or use of other chemotherapy agents.51 Certain T-cell-depleting agents (e.g. alemtuzumab) will also place patients at a higher risk of PJP, particularly if salvage treatment is being administered.52 Further, patients who have had PJP previously remain at high risk of a subsequent episode if their underlying immune deficit persists. Patients in whom the risk of PJP is not conclusively established, but is likely to be moderate, include those with autologous bone marrow transplant,3 and patients © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Guidelines for prevention and treatment of PJP

with haematological malignancy undergoing certain high-intensity chemotherapy regimens. In the latter case, clinicians should be particularly vigilant of R-CHOP14 (rituximab, cyclophosphamide, adriamycin, vincristine, prednisolone chemotherapy on a 14-day cycle),38,40,42,43,53 FCR (fludarabine, cyclophosphamide, rituximab),27 AVBD (adriamycin, vincristine, bleomycin, dexamethasone),54 gemcitabine55 and high-dose methotrexate. Patients with prolonged CD4 lymphopenia, before or after initiation of chemotherapy, are also likely to be at moderate risk of PJP. However, with limited evidence to assess PJP risk in this group, debate still surrounds the use of prophylaxis in this population.56,57 Patients with haematological malignancy at lower risk of PJP include those receiving low-intensity chemotherapy regimens (such as R-CHOP given on a 21-day cycle), provided they do not have other risk factors.38,45,46,58

patients, depending on density of dosing.67,68 In a phase 2 trial, 79% of patients developed grade 3–4 lymphopenia, with two of the first 15 patients (13%) developing PJP.69 Subsequent cases have led to a black-box warning recommending that PJP prophylaxis accompany the use of this agent.7,59,70 Collectively, these data suggest that PJP prophylaxis should be considered in solid-tumour patients undergoing chemotherapy regimens containing 16–25 mg prednisolone or ≥4 mg dexamethasone daily for ≥4 weeks, as well as patients undergoing intensive treatment for cerebral malignancy (grade C recommendation). Prophylaxis should be continued for 6 weeks after the steroidtapering period. A summary of agents for PJP prophylaxis and their indications for use are provided in Table 2.

Chemoprophylaxis for PJP TMP-SMX

PJP risk in patients with solid-organ malignancy PJP has been reported to occur in patients undergoing chemotherapy for a broad range of solid-organ malignancies, including breast, pulmonary, renal, genitourinary and colorectal cancer; central nervous system tumours; rhabdomyosarcoma and melanoma.4,7,59–61 Despite this, there are no clinical efficacy data supporting the routine use of PJP prophylaxis in these patient groups. The inclusion of corticosteroid therapy in the chemotherapy regimen has been consistently reported as a risk factor for developing PJP in adult patients with solidorgan tumours.7,61–63 Adult patients who are receiving high-dose corticosteroid therapy (16–25 mg prednisolone or ≥4 mg dexamethasone daily for ≥4 weeks) appear to be at greatest risk, both during high-dose therapy and the steroid-tapering period.59 Patients receiving these kinds of doses are typically undergoing dose-intensive chemotherapy for lung, breast or brain cancer. There is a paucity of data in the paediatrics setting, although a dosage equivalent to ≥2 mg/kg per day of prednisone or equivalent to a total of ≥20 mg/day for children who weigh more than 10 kg, particularly when given for more than 14 days, is considered to be T-cell immunosuppressive.64 Patients with brain tumours are at particular risk of PJP. While the incidence of PJP is low (1.7%) among patients receiving corticosteroids for brain tumours,65 cranial irradiation increases the risk of PJP. Over a 12-month period, PJP has a reported incidence of 6.2% in this population, with a median time to onset of 10 weeks.66 Temozolomide, an alkylating agent used for the treatment of glioblastoma multiforme, results in significant lymphopenia (35 mmHg or an arterial oxygen pressure 70 mmHg) may benefit from corticosteroids, but a difference in respiratory failure and death has not been demonstrated. Studies in non-HIV-infected patients have produced conflicting results. Retrospective studies3,103,104 showed no benefit in non-HIV-infected patients with moderate to severe disease. In contrast, Pareja et al.105 found patients who received adjunctive steroids required shorter duration of mechanical ventilation and ICU admission, and © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Guidelines for prevention and treatment of PJP

Table 4 Recommended dosing for treatment of Pneumocystis jirovecii infection† Adult

Child

Comments

TMP-SMX

5 + 25 mg/kg oral or IV, 8-hourly for 21 days In severe disease, increase to 6-hourly initially

>1 month Dose as for adult

First-line therapy for all levels of severity Consider desensitisation except with known history of immediate hypersensitivity or TEN/SJS

Clindamycin plus primaquine

450 mg clindamycin orally, 8-hourly PLUS 15 mg primaquine orally, daily for 21 days In severe disease, increase clindamycin to 900mg IV, 8-hourly initially then dose as above. Also, increase primaquine to 30 mg

10 mg/kg (max 450 mg) clindamycin orally 8-hourly PLUS 0.25 mg/kg primaquine (max 15 mg) orally, daily for 21 days

Second-line therapy for severe disease Test for G6PD deficiency before treatment with primaquine

Pentamidine

In severe disease where TMP-SMX contraindicated: pentamidine 4 mg/kg (max 300 mg) IV, daily for 21 days

In severe disease where TMP-SMX contraindicated: pentamidine 4 mg/kg (max 300 mg) IV, daily for 21 days

Equal second-line therapy for severe disease

Dapsone plus trimethoprim

100 mg dapsone orally, daily PLUS 5 mg/kg trimethoprim orally, 8-hourly for 21 days

2 mg/kg dapsone (max 100 mg) orally, daily PLUS 5 mg/kg trimethoprim orally, 8-hourly for 21 days

Alternative option as first line therapy for mild-moderate disease There is 20% cross-reaction with sulfonamides and dapsone; contraindicated with immediate hypersensitivity or severe reactions. Consider testing for G6PD deficiency prior to use.

Atovaquone

For mild-moderate diseases: 750 mg orally, 12-hourly for 21 days

24 months: 15–20 mg/kg orally, daily; 3–24 months: 22.5 mg/kg orally, 12-hourly for 21 days

Third-line therapy

†Refer to Therapeutic Guidelines: antibiotic (version 15) for further details.94 SJS, Stevens Johnson Syndrome; TEN, toxic epidermal necrolysis.

reduced supplemental oxygen use. No differences in the rates of intubation or in-hospital mortality were observed. Although there are insufficient data to make a recommendation regarding the use of adjuvant corticosteroids in patients with PJP and malignancy, it may be appropriate to co-administer corticosteroids, at doses used in HIVassociated PJP, in patients with moderate to severe PCP.

Alternative agents for the treatment of PJP in the setting of TMP-SMX intolerance Desensitisation should be considered for all patients with TMP-SMX-associated rash but is contraindicated in those with a prior history of associated drug rash with eosinophilia and systemic symptoms (‘DRESS’), StevensJohnson syndrome or toxic epidermal necrolysis. If TMPSMX remains contraindicated, alternative agents include atovaquone, clindamycin plus primaquine and dapsone plus trimethoprim, although there is extremely limited evidence for efficacy in children, and limited data for safety in children with cancer (grade D recommendation). Few clinical studies have assessed second-line therapies in patients with malignancy. Therefore, recommendations for second-line therapy are based on data © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

from clinical studies involving HIV-infected individuals and are in concordance with the current version of Therapeutic Guidelines: antibiotic, version 15.94 Intravenous pentamidine has been shown to have similar efficacy to TMP-SMX in HIV-infected individuals with PJP.106,107 A retrospective review of first- and secondline therapy for HIV-associated PJP108 found higher rates of unchanged second-line therapy with pentamidine than with TMP-SMX; however, survival rates were significantly lower when compared with TMP-SMX and clindamycin-primaquine. Pentamidine was associated with a higher risk of death (RR 3.3, 95% CI 2.2–5.0). A comparison of aerosolised and reduced-dose intravenous pentamidine therapy in patients with mild to moderate disease found higher rates of early recrudescence and relapse in the aerosolised group.109 Clindamycin-primaquine was compared with TMPSMX in a randomised study of mild and moderately severe PJP in HIV-infected individuals.110 In a study limited by sample size, efficacy of clindamycinprimaquine was similar to oral TMP-SMX or dapsonetrimethoprim for treatment of mild-moderate PJP in HIV-infected individuals in terms of dose-limiting toxicity, therapeutic failure or survival.95 Notably, serious

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haematological toxicity (neutropenia, thrombocytopenia and methemoglobinaemia) was more common in the clindamycin-primaquine arm. While dapsone has been shown to be an ineffective treatment as a single agent, a combination of oral dapsone plus trimethoprim was effective in patients with HIV-associated PJP.111 Major toxicity was seen in only 13% of patients. Dapsone-trimethoprim has been shown to be equivalent to TMP-SMX and clindamycinprimaquine in mild-moderate disease.95 Atovaquone (750 mg TDS) has been compared with TMP-SMX in a randomised trial of HIV-infected individuals with mild-moderate PJP.96 Non-response rates were significantly higher in the atovaquone arm, although tolerability was greater than with TMP-SMX. Overall successful therapy, defined by clinical response and no adverse events, was equivalent. Animal studies have demonstrated that echinocandins, which target ß(1,3)-D-glucan, have activity against P. jirovecii;112 however, clinical trials in humans have not been performed. Data regarding efficacy are restricted to case reports, and these have revealed inconsistent responses.113–116 Echinocandins cannot be recommended at this time due to their high cost, lack of an oral formulation and the absence of compelling evidence demonstrating their efficacy (grade D recommendation).

Managing PJP treatment failure Clinical failure is defined as lack of improvement or worsening of respiratory function documented by reduced arterial oxygen saturation after at least 4–8 days of Pneumocystis treatment. Early and reversible deterioration in the first 3–5 days is typical, and clinicians should wait at least 4–8 days before changing therapy due to lack of improvement. Although evidence is limited, intravenous pentamidine, clindamycin-primaquine or addition of an echinocandin can be considered for salvage therapy in cases of treatment failure.117 Treatment failure due to drug intolerance appears less common in malignancy-associated PJP than in HIV infection. Relapse has been reported only rarely in non-HIV associated PJP.

outbreaks of infection among kidney transplant patients.118–121 The predominant method of spread for Pneumocystis is believed to be person-to-person transmission through exhaled air. Airborne transmission has been demonstrated in animal studies, and air samples from the rooms of patients with PJP have shown the presence of like organisms in air as far as 8 metres from the patient, suggesting that this may be a route of transmission.122–124 It is possible that symptomatic patients might be at higher risk of transmission because of apparent higher density of colonisation.17,125 Staff members and other patients may be at risk of becoming colonised from direct or indirect contact with an infected patient.126 However, colonisation of healthy humans and previously infected patients is frequent, without placing individuals at risk of subsequent infection. Most cases of PJP occur sporadically, without a known infected contact.127,128 PJP outbreaks in other patient populations (predominantly renal transplantation) have been reported, suggesting person-to-person transmission on the basis of epidemiology and molecular testing.119,125,129–131 However, epidemiologically distinct cases with identical molecular types may also occur.118 While some clinicians and institutions recommend that at-risk patients should not share a hospital room with a patient with known PJP, the current evidence is insufficient to mandate isolation in haematology and solidtumour groups. It is important that patients at risk of PJP are identified and receive prophylaxis.

Conclusion Patients with haematological and solid-organ tumours are highly susceptible to PJP due to disease- and treatment-related immunosuppression. In this patient population, PJP is associated with high morbidity and mortality. Appropriate prophylaxis for all moderate- to high-risk patients is a key strategy for improving outcomes, given the proven efficacy of this approach. TMPSMX is the drug of choice for both prophylaxis and treatment, although several alternative agents are available, as outlined here.

PJP infection-prevention measures

Acknowledgements

A role for isolation precautions to prevent inter-patient transmission of PJP has not been established for patients with malignancy, although there are data that suggest good infection-control measures prevent transmission in

The authors would like to thank members of ALLG, ASID and ANZCHOG for their review of the draft document, and Dr Candice O’Sullivan from Wellmark Pty Ltd for her assistance in preparing the manuscript for submission.

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